Leucine suppresses glucagon secretion from pancreatic islets by directly modulating α-cell cAMP DOI Creative Commons
Emily R. Knuth, Hannah R. Foster,

Erli Jin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: July 31, 2023

Abstract Objective Pancreatic islets are nutrient sensors that regulate organismal blood glucose homeostasis. Glucagon release from the pancreatic α-cell is important under fasted, fed, and hypoglycemic conditions, yet metabolic regulation of α-cells remains poorly understood. Here, we identified a previously unexplored role for physiological levels leucine, which classically regarded as β-cell fuel, in intrinsic glucagon release. Methods GcgCre ERT :CAMPER :GCaMP6s mice were generated to perform dynamic, high-throughput functional measurements cAMP Ca 2+ within intact islet. Islet perifusion assays used simultaneous, time-resolved insulin mouse human islets. The effects leucine compared with mitochondrial fuels 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH, non-metabolized analog activates glutamate dehydrogenase), α-ketoisocaproate (KIC, metabolite), methyl-succinate (complex II fuel). CYN154806 (Sstr2 antagonist), diazoxide (K ATP activator, prevents -dependent exocytosis α, β, δ-cells), dispersed inhibit islet paracrine signaling identify effects. Results Mimicking effect glucose, strongly suppressed amino acid-stimulated secretion. Mechanistically, dose-dependently reduced at concentrations, an IC 50 57, 440, 1162 μM 2, 6, 10 mM without affecting . Leucine also treated Sstr2 antagonist or diazoxide, well α-cells, indicating effect. was matched by KIC dehydrogenase activator BCH, but not methyl-succinate, dependence on anaplerosis. Glucose, stimulates anaplerosis via pyruvate carboxylase, had same suppressive lower potency. Similarly islets, secretion conditions. Conclusions These findings highlight functions primarily through dependent dehydrogenase, addition well-established β/δ-cell signaling. Our results suggest anaplerosis-cataplerosis facilitates glucagonostatic both cooperatively suppress tone reducing cAMP. Graphical Highlights inhibits suppresses direct Anaplerosis sufficient more potently than

Language: Английский

Mitochondrial membrane lipids in the regulation of bioenergetic flux DOI Creative Commons

Stephen Thomas Decker,

Katsuhiko Funai

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 1963 - 1978

Published: Aug. 23, 2024

SummaryOxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by biosynthetic machinery localized in IMM class-specific transporters that limit traffic out of mitochondria. This unique composition appears to be essential for functions mitochondria, particularly OXPHOS, its effects on direct lipid-to-protein interactions, properties, cristae ultrastructure. review highlights biological significance lipids, with particular spotlight role lipids bioenergetics. We describe pathways biosynthesis provide evidence their roles physiology, implications human disease, mechanisms which they regulate

Language: Английский

Citations

17
Glucose Regulation of β-Cell KATP Channels: Is a New Model Needed? DOI Open Access
Guy A. Rutter, Ian R. Sweet

Diabetes, Journal Year: 2024, Volume and Issue: 73(6), P. 849 - 855

Published: April 19, 2024

The canonical model of glucose-induced increase in insulin secretion involves the metabolism glucose via glycolysis and citrate cycle, resulting increased ATP synthesis by respiratory chain closure ATP-sensitive K+ (KATP) channels. plasma membrane depolarization, followed Ca2+ influx through L-type channels, then induces granule fusion. Merrins colleagues have recently proposed an alternative whereby KATP channels are controlled pyruvate kinase, using glycolytic mitochondrial phosphoenolpyruvate (PEP) to generate microdomains high ATP/ADP immediately adjacent This presents several challenges. First, how mitochondrially generated PEP, but not produced abundantly F1F0-ATP synthase, can gain access is unclear. Second, fluctuations imaged beneath closely resemble those bulk cytosol. Third, ADP privation at glucose, suggested drive alternating, phased-locked generation mitochondria or has yet be directly demonstrated. Finally, approaches used explore these questions may complicated off-target effects. We suggest instead that changes, well known affect both consumption, likely cytosolic oscillations turn regulate potential. Thus, it remains demonstrated a new required replace existing, bioenergetics–based model.

Language: Английский

Citations

11
Exploring pancreatic beta-cell subgroups and their connectivity DOI Creative Commons
Guy A. Rutter, Anne Gresch, Luis Fernando Delgadillo-Silva

et al.

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(11), P. 2039 - 2053

Published: Aug. 8, 2024

Language: Английский

Citations

10
Mitochondrial bioenergetics, metabolism, and beyond in pancreatic β-cells and diabetes DOI Creative Commons

Alejandra María Rivera Nieves,

Brian Michael Wauford,

Accalia Fu

et al.

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Feb. 9, 2024

In Type 1 and 2 diabetes, pancreatic β-cell survival function are impaired. Additional etiologies of diabetes include dysfunction in insulin-sensing hepatic, muscle, adipose tissues as well immune cells. An important determinant metabolic health across these various is mitochondria structure. This review focuses on the role pathogenesis, with a specific emphasis β-cells. These dynamic organelles obligate for survival, function, replication, insulin production, control over release. Therefore, it not surprising that severely defective diabetic contexts. Mitochondrial poses challenges to assess cause-effect studies, prompting us assemble deliberate evidence cause or consequence diabetes. Understanding precise molecular mechanisms underlying mitochondrial identifying therapeutic strategies restore homeostasis enhance active expanding areas research. summary, this examines multidimensional focusing β-cells highlighting significance metabolism, bioenergetics, calcium, dynamics, mitophagy pathophysiology We describe effects diabetes-related gluco/lipotoxic, oxidative inflammation stress mitochondria, played by pathologic outcomes paradigms. By examining aspects, we provide updated insights highlight where further research required deeper understanding

Language: Английский

Citations

9
Unravelling the complexity of the mitochondrial Ca2+ uniporter: regulation, tissue specificity, and physiological implications DOI Creative Commons
Denis Vecellio Reane, Julian D. C. Serna, Anna Raffaello

et al.

Cell Calcium, Journal Year: 2024, Volume and Issue: 121, P. 102907 - 102907

Published: May 23, 2024

Calcium (Ca

Language: Английский

Citations

6
Unique features of β‐cell metabolism are lost in type 2 diabetes DOI Creative Commons

Felipe Muñoz,

Malin Fex, Thomas Möritz

et al.

Acta Physiologica, Journal Year: 2024, Volume and Issue: 240(6)

Published: April 24, 2024

Abstract Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood levels and respond by secreting insulin. Upon stimulating uptake insulin‐sensitive tissues post‐prandially, this anabolic hormone restores to pre‐prandial levels. Maintaining physiological thus relies on proper β‐cell function. To fulfill highly specialized nutrient sensor role, have evolved a unique genetic program that shapes its distinct cellular metabolism. In review, metabolic features will be outlined, including their alterations type 2 diabetes (T2D). selectively express set genes cell type‐specific manner; for instance, activating hexokinase IV enzyme or Glucokinase ( GCK ), whereas other are “disallowed”, lactate dehydrogenase A LDHA ) monocarboxylate transporter 1 MCT1 ). This selective gene equips with apparatus ensure metabolism is coupled appropriate insulin secretion, thereby avoiding hyperglycemia, well life‐threatening hypoglycemia. Unlike most types, exhibit bioenergetic features, supply‐driven rather than demand‐driven high basal mitochondrial proton leak respiration. The understanding these genetically programmed lead dysfunction crucial comprehensive T2D pathophysiology development innovative therapeutic approaches patients.

Language: Английский

Citations

5
Exploring new mechanisms of Imeglimin in diabetes treatment: Amelioration of mitochondrial dysfunction DOI Open Access
Yilin Li,

N. Lou,

Xiaojing Liu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 175, P. 116755 - 116755

Published: May 20, 2024

With the increasing prevalence of type 2 diabetes mellitus (T2DM), it has become critical to identify effective treatment strategies. In recent years, novel oral hypoglycaemic drug Imeglimin attracted much attention in field treatment. The mechanisms its therapeutic action are complex and not yet fully understood by current research. Current evidence suggests that pancreatic β-cells, liver, skeletal muscle main organs which lowers blood glucose levels acts mainly targeting mitochondrial function, thereby inhibiting hepatic gluconeogenesis, enhancing insulin sensitivity, promoting β-cell regulating energy metabolism. There is growing also a potentially volatile role diabetic complications, including metabolic cardiomyopathy, vasculopathy, neuroinflammation. According available clinical studies, efficacy safety profile more evident than other agents, synergistic effects when combined with antidiabetic drugs, potential T2DM-related complications. This review aims shed light on latest research progress T2DM Imeglimin, providing clinicians researchers insights into as viable option for T2DM.

Language: Английский

Citations

5
Islet Transplantation: Current Limitations and Challenges for Successful Outcomes DOI Creative Commons
A. Langlois,

M. Pinget,

L. Kessler

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(21), P. 1783 - 1783

Published: Oct. 28, 2024

Islet transplantation is a promising approach for treating patients with unstable T1DM. However, it confronted numerous obstacles throughout the various stages of procedure. Significant progress has been made over last 25 years in understanding mechanisms behind loss functional islet mass and developing protective strategies. Nevertheless, at present, two to three pancreases are still needed treat single patient, which limits maximal number who can benefit from transplantation. Thus, this publication provides an overview recent scientific findings on issues affecting Specifically, we will focus involved strategies developed alleviate these problems isolation stage post-transplantation phase. Finally, hope that review highlight new avenues action, enabling us propose pancreatic maximum

Language: Английский

Citations

5
Mitochondrial redox state, bioenergetics, and calcium transport in caloric restriction: A metabolic nexus DOI
Eloisa Aparecida Vilas‐Boas, Alicia J. Kowaltowski

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 219, P. 195 - 214

Published: April 25, 2024

Language: Английский

Citations

4
An inter-organelle contact between endosomal GLP-1R, ER VAP-B, and the mitochondrial AKAP SPHKAP triggers PKA-dependent MIC19 phosphorylation and β-cell mitochondrial remodelling DOI
Gregory L. Austin, Liliane El Eid, Affiong I Oqua

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 30, 2024

Abstract Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing its turnover and improving quality control. While the GLP-1R is well known to stimulate cAMP production leading activation of Protein Kinase A (PKA) Exchange Activated cyclic AMP 2 (Epac2) signalling, there a lack understanding molecular mechanisms linking GLP-1RA-induced signalling with remodelling improved function. Here we present dataset that demonstrates that, following GLP-1RA stimulation in pancreatic β-cells, interacts endoplasmic reticulum (ER) membrane contact site (MCS) organising factor VAP-B from an endocytic location engage SPHKAP, A-kinase anchoring protein (AKAP) associated type diabetes (T2D) adiposity genome-wide association studies (GWAS), trigger pool mitochondrially localised PKA phosphorylates cristae organizing system (MICOS) complex component MIC19, enabling optimal β-cell

Language: Английский

Citations

4